Research

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Xue Sean Li, PhD

Sean Li PhD
Department:
Urology Research
Hospital Title:
Principal Investigator
Academic Title:
Assistant Professor of Surgery, Harvard Medical School
Research Focus Area:
Organ morphogenesis and developmentUrothelial regenerationBladder cancer pathogenesis
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Research Overview

Sexual Dimorphism of the Lower Urinary Tract: Unlike amphibians, birds and reptiles, the cloaca of placental mammals is divided during embryogenesis such that the mature urinary and digestive tracts have separate outlets. We have recently gained insights into mammalian cloaca development using high-resolution episcopic microscopy and mouse mutants. We have now obtained convincing “visual” evidence, of which the detailed 3-dimensional (3-D) morphological features of mouse cloaca are illuminated throughout the developmental stages, to support the occlusion model. Ongoing studies aim to determine mechanisms underlying formation of the bladder and urethral tube after cloaca septation. We are particularly interested in the molecular basis of dimorphic development of external genital tubercle and human disorders of sex development (DSD).

Bladder Cancer: Bladder cancer (BCa) is the fourth most common cancer among men and the sixth overall in the world. Surprisingly, men are 3-4 times more likely to develop BCa than women are. The underlying mechanism of sex disparities in cancer incidence remains to be defined. Using innovative approaches, including genomics, genetics and CRISPR/cas9 syste, we are actively investigating genetic and epigenetic basis of gender difference in BCa susceptibility. Our preliminary findings suggest that in addition to sex hormones the sex chromosome complement plays central role in BCa development and sex disparities.

Urinary Incontinence (UI) and bladder pain syndrome: Mutation of human HPSE2 is linked to Urofacial syndrome (UFS, aka Ochoa syndrome), a rare autosomal recessive birth defect with a severe UI phenotype. We show that Hpse2-/- mice display a distended bladder (megacystis) phenotype and abnormal voiding behavior similar to that found in patients. Using this novel mouse model and molecular tools, we aim to understand the neuronal basis of voiding behavior and bladder pain syndrome.

Urinary Tract Infection and Urothelial Regeneration: Urinary tract infections (UTI) are the most common bacterial infection worldwide and are responsible for considerable morbidity, especially among women and senior citizens. Uropathogenic E. coli (UPEC) accounts for up to 90% of all UTI. Under physiologic conditions, the urothelium has a very slow turnover rate. Following UPEC infection, these quiescent urothelial cells are awakened and undergo extensive proliferation to repair the urothelial barrier. The ability of urothelium to seamlessly switch between resting and proliferative states implies that urothelium is “poised” for regeneration and repair. However, the underlying mechanism remains to be elucidated. Using specific mouse genetic tools and infection models we are currently addressing the role of epigenetic mechanisms in regulation of urothelial regeneration and repair in response to UTI.

Formation of the Great Arteries: Congenital heart disease (CHD), the most common birth defect and the leading cause of infant mortality. Formation of the cardiac outflow tract (OFT) is particularly complex and prone to error: OFT anomalies are found in nearly 1/3 of CHD patients. Despite its frequent involvement in CHD, the origins and patterning of the mammalian OFT remain partially understood. We have recently gained insights into mammalian OFT development through our studies of Six-family transcription factors, and their Eya-family transcriptional co-factors. Contrary to the popular belief that septation of the conotruncus results in formation of the two arterial trunks, our findings show that the arterial trunks are in fact entirely different structures. Our current working model is that the mammalian cardiac OFT is formed by adding new components, i.e., the arterial trunks, while concurrently remodeling preexisting structures including the conotruncus.

Key Publications

See a complete list of published work in my bibliography.

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